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Utilizing a Microfluidic Platform to Investigate Drug-Eluting Beads: Binding and Release of Amphiphilic Antidepressants
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Pharmaceutical Physical Chemistry)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Pharmaceutical Physical Chemistry)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Pharmaceutical Physical Chemistry)ORCID iD: 0000-0002-0895-1180
2023 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 647, article id 123517Article in journal (Refereed) Published
Abstract [en]

Drug-eluting beads made of responsive polyelectrolyte networks are used in the treatment of liver cancer. Aggregates of loaded drugs in complex with the networks dissolve upon release, causing swelling of the network. According to a recent mechanism the release and swelling rates are controlled by the mass transport of drug through a depletion layer created in the microgel. We hypothesise that the mechanism, in which the stability of the drug aggregates and the swelling properties of the network play crucial roles, offers means to control the release profile also for other drugs. To test this, we investigated the loading and release properties of amitriptyline, chlorpromazine and doxepin in polyacrylate, hyaluronate and DCbeadTM microgels in a microfluidic setup. Loaded drugs could be released to a medium with physiological ionic strength and pH. The binding strength increased with decreasing critical micelle concentration of the drugs and increasing linear charge density of network chains. Microgels displayed drug-rich core/swollen shell coexistence, and swelled during release at a rate in agreement with the depletion layer mechanism, indicating its generality. The results demonstrate the potential of microgels as vehicles for amphiphilic drugs and the usefulness of the microfluidics method for in vitro studies of such systems.

Place, publisher, year, edition, pages
Elsevier, 2023. Vol. 647, article id 123517
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry; Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-509095DOI: 10.1016/j.ijpharm.2023.123517ISI: 001102355600001PubMedID: 37871867OAI: oai:DiVA.org:uu-509095DiVA, id: diva2:1787811
Funder
Vinnova, 2019-00048Available from: 2023-08-15 Created: 2023-08-15 Last updated: 2023-12-11Bibliographically approved
In thesis
1. Development and characterization of an in vitro method for interaction studies between polymers and pharmaceuticals: Aiding in the development of new drug delivery systems
Open this publication in new window or tab >>Development and characterization of an in vitro method for interaction studies between polymers and pharmaceuticals: Aiding in the development of new drug delivery systems
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Polymers are a group of macromolecules used in formulations of pharmaceuticals, one example being the delivery system DC Bead™. Further, some of the most abundant and for drug delivery important constituents of the subcutaneous tissue are charged polymers (polyelectrolytes), e.g. collagen, hyaluronic acid, and chondroitin sulfate. The interactions between these subcutaneous polyelectrolytes and drug molecules are believed to heavily affect the transport and absorption of subcutaneously injected drugs. To increase the understanding of how the interactions between subcutaneous polymers and drug molecules affect the pharmaceutical behavior in subcutaneous tissue, we developed a new microfluidic-based platform. The platform is used to study interactions between polyelectrolytes and drug molecules, and can beyond the investigation of subcutaneous interactions be used to develop polyelectrolyte-based microgel formulations. In this thesis, the microfluidic method denoted “Microfluidic chip for interactions studies” (MIS) is presented, and the design, validation, and several examples of usage are described. The method which is based on microfluidic instrumentation, utilizes spherical microgels created using different types of polymers/polyelectrolytes. These hydrogels collapse when experiencing attractive interactions with drug molecules making it possible to investigate drug binding by studying the volume change of the microgels. We prove that the interactions are strongly affected by charges both on the gel networks and the drug molecules. Further, the aggregation behavior of drugs in a polyelectrolyte-rich environment is studied in detail. Results show that both a strong aggregation behavior and a high charge on the drugs may affect the transport through a network of polyelectrolytes. The behavior of drugs in subcutaneous polyelectrolyte-rich environments such as hyaluronic acid networks, can partly explain bioavailability and absorption rates of the drugs in vivo. Several potential drug delivery systems in the form of microgels were investigated together with both small amphiphilic molecules and larger peptides exhibiting a wide range of physicochemical properties. The results indicate a possibility of delivering large amounts of drug in low volumes of microgel suspensions but with varying release times, ranging from seconds to days. The MIS was able to provide information about the interactions in a large number of polyelectrolyte-drug systems. The studies were performed in a highly efficient and cost-effective way, with experiments being mostly automated. This makes it a suitable method for rapid screening experiments in the development of new microgel formulations, and as part of larger studies utilizing several different methods to better understand and predict the behavior and absorption profiles of potential subcutaneously administrated drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2023. p. 88
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 338
Keywords
Microgels, Subcutaneous administration, Drug delivery, Microfluidics, In vitro methodology, Method development, Biopharmaceuticals, Amphiphilic drugs, Polyelectrolytes, Hyaluronic acid, Peptides
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-509384 (URN)978-91-513-1888-2 (ISBN)
Public defence
2023-10-20, Room A1:107a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2023-09-28 Created: 2023-09-01 Last updated: 2023-09-28

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Wanselius, MarcusAl-Tikriti, YassirHansson, Per

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